Plasma levels of high density lipoprotein (HDL) cholesterol are inversely associated with risk of atherosclerotic cardiovascular disease in humans, and preclinical studies have consistently demonstrated that intervention to raise HDL inhibits progression or induces regression of atherosclerosis (1). HDL is believed to protect against atherosclerosis by promoting reverse cholesterol transport (2), as well as potentially through a variety of other protective properties. However, despite advances over the last decade, the molecular regulation of HDL metabolism and reverse cholesterol transport (RCT) remain incompletely understood, the relevance of other HDL properties remains uncertain, and the concept of directly targeting HDL therapeutically in humans remains unproven (3). There are relatively few validated targets for developing novel therapeutic approaches targeted toward HDL (4). The most advanced, CETP inhibition, has come into question as a therapeutic strategy (5). Recent genome-wide association studies (GWAS) have begun to identify previously unsuspected genes involved in regulating HDL-C levels, and have also established that all three members of the subfamily of extracellular lipases that act on lipoproteins, lipoprotein lipase (LPL), hepatic lipase (HL), and endothelial lipase (EL), are significantly associated with variation in HDL-C levels. Clearly this subfamily plays a key role in modulating HDL metabolism, as well as risk of atherosclerosis. However, the detailed mechanisms by which these lipases influence HDL metabolism, the environmental and genetic factors that regulate their expression, and the other gene products they interact with to regulate HDL metabolism and function remain incompletely understood. We propose to address the interactions of EL with HL in modulating HDL metabolism and atherogenesis, the interactions of EL and HL with the lipid transfer proteins cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), the implications and mechanisms of upregulation of EL activity in the obese insulin resistant state, and the regulation of HDL metabolism through naturally-occurring genetic polymorphisms in the coding region and promoter of the EL gene. These studies span biochemical, cell biology, mouse, and human translational studies in an effort to address the questions. This subfamily of lipases is a potential target for novel therapeutic development, and these studies will provide greater understanding of their effects on HDL metabolism and function, enabling future treatments to prevent atherosclerosis.